ABSTRACT Smoking is the leading cause of preventable death in the United States. In 2009, the Food and Drug Administration was given the authority to regulate tobacco products, including the authority to reduce the nicotine content of cigarettes to any non-zero level. A drastic reduction in nicotine content could reduce the prevalence of smoking. However, one of the primary concerns regarding nicotine reduction is that smokers would increase their smoke intake?either through increasing the number of cigarettes smoked per day or changing the way they smoke?to obtain more nicotine. Nicotine reduction clinical trials have generally not found evidence of compensatory smoking. However, most participants in low nicotine groups use non-study cigarettes, despite explicit instructions to use only the study cigarettes provided to them. Thus, it is possible that an FDA-mandated reduction in the nicotine content of cigarettes could lead to compensatory smoking when normal nicotine content cigarettes are no longer available for purchase. The aim of the proposed study is to test the impact of nicotine reduction on smoking behavior and toxicant exposure when participants do not have access to normal nicotine content cigarettes. Twenty participants will be confined to a hotel setting for two four-night stays during which time they only have access to the investigational cigarettes provided to them. During one hotel stay they will have access to investigational normal nicotine content cigarettes, and during the other hotel stay they will only have access to investigational very low nicotine content cigarettes. To assess whether smokers engage in compensatory smoking as a result of nicotine reduction, biomarkers of smoke and toxicant exposure (urinary mercapturic acids, expired carbon monoxide) and behavioral measures of smoking (cigarettes smoked per day, puff topography) will be compared between the two conditions.